title: Enhancement of cisplatin-based TACE by a hemoglobin-based oxygen carrier in an orthotopic rat HCC model.
abstract: OBJECTIVE
  Hypoxic tumor cells are more resistant to standard chemotherapies. A number of studies indicated that improving oxygenation inside the tumor could serve as a potential strategy to target hypoxia-induced chemoresistance. In this study, we examined whether a hemoglobin-based oxygen carrier (OC89) could increase tumor oxygenation and thus enhance the efficiency of transarterial chemoembolization (TACE) in an orthotopic rat HCC model.
  
  
  METHODS
  Efficiency of the hemoglobin-based oxygen carrier (OC89) in improving tumor oxygenation was examined by OxyLab pO2. Sensitization of chemotherapy (cisplatin) in TACE by OC89 was evaluated in four different therapeutic regimens including cisplatin (1 mg/kg)+OC89 (0.2 g/kg), cisplatin (1 mg/kg)+OC89 (0.4 g/kg), cisplatin (3 mg/kg)+OC89 (0.2 g/kg), cisplatin (3 mg/kg)+OC89 (0.4 g/kg). For all the therapeutic regimens, a single delivery of OC89 via the tail vein was performed 1 h before TACE.
  
  
  RESULTS
  Compared with Ringer's buffer, systemic delivery of OC89 (0.4 g/kg) attenuated tumor hypoxia (p<0.05). Additionally, partial pressure of oxygen (pO2) fraction of low readings (0-10 mmHg) inside the tumor decreased from 74.1% to 24.6% after OC89 delivery, while pO2 fraction of high readings (15-25 mmHg) increased from 22.2% to 41.5%. When cisplatin was combined with OC89, regimen cisplatin (3 mg/kg)+OC89 (0.4 g/kg) resulted in a significant inhibition of tumor growth at Day 21 after therapy (p<0.05). Further investigation indicated that OC89 delivery influenced anti-apoptotic and pro-apoptotic balance of the UPR pathway in the tumor.
  
  
  CONCLUSIONS
  Our data suggest that targeting tumor hypoxia with the hemoglobin-based O2 carrier serves as a promising approach to enhance the efficacy of cisplatin-based chemotherapy in HCC.
authors.affiliation: Department of Surgery, the Hong Kong University , Hong Kong.
authors.forename: Xiao-Bing
authors.initials: XB
authors.lastname: Liu
authors.forename: Qiao
authors.initials: Q
authors.lastname: Cheng
authors.forename: Wei
authors.initials: W
authors.lastname: Geng
authors.forename: Chang-Chun
authors.initials: CC
authors.lastname: Ling
authors.forename: Yan
authors.initials: Y
authors.lastname: Liu
authors.forename: Kevin Tak-Pan
authors.initials: KT
authors.lastname: Ng
authors.forename: Judy Wai-Ping
authors.initials: JW
authors.lastname: Yam
authors.forename: Xin-Yuan
authors.initials: XY
authors.lastname: Guan
authors.forename: Chung-Mau
authors.initials: CM
authors.lastname: Lo
authors.forename: Kwan
authors.initials: K
authors.lastname: Man
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001802:Blood Substitutes / Q000494:pharmacology*; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000378:metabolism / Q000473:pathology* / Q000628:therapy; D002417:Cattle; D015687:Cell Hypoxia / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D016461:Chemoembolization, Therapeutic; D002945:Cisplatin / Q000494:pharmacology* / Q000627:therapeutic use; D004195:Disease Models, Animal; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004357:Drug Synergism; D000091342:Endoplasmic Reticulum Chaperone BiP; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006360:Heat-Shock Proteins / Q000235:genetics; D006454:Hemoglobins / Q000494:pharmacology*; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology* / Q000628:therapy; D010100:Oxygen / Q000378:metabolism*; D051381:Rats; D056811:Unfolded Protein Response / Q000187:drug effects
chemical_list: D001802:Blood Substitutes; D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; D006360:Heat-Shock Proteins; D006454:Hemoglobins; D002945:Cisplatin; D010100:Oxygen
keywords: GRP78; UPR pathway; chemoresistance; hypoxia; oxyLab pO2; oxygenation